In vitro phototoxicity of ultradeformable liposomes containing chloroaluminum phthalocyanine against New World Leishmania species

Abstract Objectives To evaluate the in vitro activity and in vivo efficacy of fexinidazole against the main species that cause visceral and cutaneous New World leishmaniasis. Methods The inhibitory concentrations of fexinidazole against Leishmania (Leishmania) infantum chagasi, Leishmania (Leishmania) amazonensis and Leishmania (Viannia) braziliensis in amastigotes were determined by in vitro activity assays. For the in vivo evaluation, animals were infected with L. (L.) infantum chagasi, L. (L.) amazonensis, L. (V.) braziliensis or Leishmania (Viannia) guyanensis and divided into groups: (i) control; and (ii) treated with oral fexinidazole, from 50 to 300 mg/kg/day. For cutaneous leishmaniasis, the size of the lesion was determined weekly after the beginning of the treatment. Upon completion, parasites were recovered from the spleen and liver, or skin lesion and spleen, and evaluated by a limiting dilution assay. Results All Leishmania isolates were susceptible to fexinidazole in the in vitro assays. The viable parasites in the liver and spleen were reduced with 100 and 300 mg/kg/day, respectively, for L. (L.) infantum chagasi. For the species causing cutaneous leishmaniasis, the viable parasites in lesions and the size of the lesions were reduced, starting from 200 mg/kg/day. The viable parasites in the spleen were also reduced with 200 and 300 mg/kg/day for L. (V.) braziliensis and L. (L.) amazonensis. Conclusions Considering the defined parameters, fexinidazole showed in vitro and in vivo activity against all tested species. This drug may represent an alternative treatment for the New World species.

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Naphthoquinones and derivatives for chemotherapy: perspectives and limitations of their anti-trypanosomatids activities

Current Pharmaceutical Design ◽

10.2174/1381612826666201109111802 ◽

2020 ◽

Vol 26 ◽

Author(s):

Luíza Dantas-Pereira ◽

Edézio F. Cunha-Junior ◽

Valter V. Andrade-Neto ◽

John F. Bower ◽

Guilherme A. M. Jardim ◽

...

Keyword(s):

Large Scale ◽

Neglected Tropical Diseases ◽

Folk Medicine ◽

Leishmania Species ◽

Parasitic Infections ◽

Mechanistic Analysis ◽

Leishmania Spp ◽

Nanomolar Range

: Chagas disease, Sleeping sickness and Leishmaniasis, caused by trypanosomatids Trypanosoma cruzi, Trypanosoma brucei and Leishmania spp., respectively, are considered neglected tropical diseases, and they especially affect impoverished populations in the developing world. The available chemotherapies are very limited and a search for alternatives is still necessary. In folk medicine, natural naphthoquinones have been employed for the treatment of a great variety of illnesses, including parasitic infections. This review is focused on the anti-trypanosomatid activity and mechanistic analysis of naphthoquinones and derivatives. Among all the series of derivatives tested in vitro, naphthoquinone-derived 1,2,3-triazoles were very active on T. cruzi infective forms in blood bank conditions, as well as in amastigotes of Leishmania spp. naphthoquinones containing a CF3 on a phenyl amine ring inhibited T. brucei proliferation in the nanomolar range, and naphthopterocarpanquinones stood out for their activity on a range of Leishmania species. Some of these compounds showed a promising selectivity index (SI) (30 to 1900), supporting further analysis in animal models. Indeed, high toxicity to the host and inactivation by blood components are crucial obstacles to be overcome to use naphthoquinones and/or their derivatives for chemotherapy. Multidisciplinary initiatives embracing medicinal chemistry, bioinformatics, biochemistry, and molecular and cellular biology need to be encouraged to allow the optimization of these compounds. Large scale automated tests are pivotal for the efficiency of the screening step, and subsequent evaluation of both the mechanism of action in vitro and pharmacokinetics in vivo are essential for the development of a novel, specific and safe derivative, minimizing adverse effects.

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Identification of Potential Kinase Inhibitors within the PI3K/AKT Pathway of Leishmania Species

Biomolecules ◽

10.3390/biom11071037 ◽

2021 ◽

Vol 11 (7) ◽

pp. 1037

Author(s):

Rodrigo Ochoa ◽

Amaya Ortega-Pajares ◽

Florencia A. Castello ◽

Federico Serral ◽

Darío Fernández Do Porto ◽

...

Keyword(s):

Kinase Inhibitors ◽

Screening Method ◽

Molecular Targets ◽

Leishmania Species ◽

Akt Pathway ◽

Protein Protein Interaction ◽

Starting Point ◽

Binding Pockets ◽

Protein Protein Interaction Networks

Leishmaniasis is a public health disease that requires the development of more effective treatments and the identification of novel molecular targets. Since blocking the PI3K/AKT pathway has been successfully studied as an effective anticancer strategy for decades, we examined whether the same approach would also be feasible in Leishmania due to their high amount and diverse set of annotated proteins. Here, we used a best reciprocal hits protocol to identify potential protein kinase homologues in an annotated human PI3K/AKT pathway. We calculated their ligandibility based on available bioactivity data of the reported homologues and modelled their 3D structures to estimate the druggability of their binding pockets. The models were used to run a virtual screening method with molecular docking. We found and studied five protein kinases in five different Leishmania species, which are AKT, CDK, AMPK, mTOR and GSK3 homologues from the studied pathways. The compounds found for different enzymes and species were analysed and suggested as starting point scaffolds for the design of inhibitors. We studied the kinases’ participation in protein–protein interaction networks, and the potential deleterious effects, if inhibited, were supported with the literature. In the case of Leishmania GSK3, an inhibitor of its human counterpart, prioritized by our method, was validated in vitro to test its anti-Leishmania activity and indirectly infer the presence of the enzyme in the parasite. The analysis contributes to improving the knowledge about the presence of similar signalling pathways in Leishmania, as well as the discovery of compounds acting against any of these kinases as potential molecular targets in the parasite.

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In Vitro and In Vivo Activities of a Triterpenoid Saponin Extract (PX-6518) from the Plant Maesa balansae against Visceral Leishmania Species

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.48.1.130-136.2004 ◽

2004 ◽

Vol 48 (1) ◽

pp. 130-136 ◽

Cited By ~ 59

Author(s):

Louis Maes ◽

Dirk Vanden Berghe ◽

Nils Germonprez ◽

Ludo Quirijnen ◽

Paul Cos ◽

...

Keyword(s):

Leishmania Donovani ◽

Human Fibroblasts ◽

Subcutaneous Administration ◽

Leishmania Species ◽

Host Cells ◽

Triterpenoid Saponin ◽

Sodium Stibogluconate ◽

Triterpenoid Saponins

ABSTRACT The in vitro and in vivo activities of a mixture of six oleane triterpene saponins, recovered from the methanolic extract of the leaves of the Vietnamese plant Maesa balansae (PX-6518), were evaluated against drug-sensitive visceral Leishmania strains. The in vitro 50% inhibitory concentration (IC50) against intracellular Leishmania infantum amastigotes was 0.04 μg/ml. The cytotoxic concentrations causing 50% cell death (CC50s) were about 1 μg/ml in murine macrophage host cells and >32 μg/ml in human fibroblasts (MRC-5 cell line). Evaluation in the Leishmania donovani BALB/c mouse model indicated that a single subcutaneous administration of 0.4 mg/kg at 1 day after infection reduced liver amastigote burdens by about 95% in all treated animals. If treatment was delayed until 14 days after infection, a dose of 1.6 mg/kg of body weight was required to maintain the same level of activity. Single 250-mg/kg doses of sodium stibogluconate (Pentostam) 1 and 14 days after infection produced comparable efficacies. A single dose of PX-6518 at 2.5 mg/kg administered 5 days before infection was still 100% effective in preventing liver infection, suggesting a particularly long residual action. Spleen and bone marrow could not be cleared by PX-6518 nor sodium stibogluconate. PX-6518 did not show activity after oral dosing at up to 200 mg/kg for 5 days. This study concludes that triterpenoid saponins from M. balansae show promising in vitro and in vivo antileishmanial potential and can be considered as new lead structures in the search for novel antileishmanial drugs.

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Axenic amastigotes of Leishmania species as a suitable model for in vitro studies

Acta Tropica ◽

10.1016/j.actatropica.2021.105956 ◽

2021 ◽

pp. 105956

Author(s):

Geovane Dias-Lopes ◽

Anabel Zabala-Peñafiel ◽

Barbara Cristina de Albuquerque-Melo ◽

Franklin Souza-Silva ◽

Laura Menaguali do Canto ◽

...

Keyword(s):

Leishmania Species ◽

In Vitro Studies ◽

Suitable Model ◽

Axenic Amastigotes

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Antiviral Therapy of Haemorrhagic Fevers and Arbovirus Infections

Antiviral Therapy ◽

10.1177/135965359800300201 ◽

1998 ◽

Vol 3 (2) ◽

pp. 53-79

Author(s):

Mike Bray ◽

John Huggins

Keyword(s):

New World ◽

Protective Efficacy ◽

Rift Valley Fever Virus ◽

Antiviral Drug ◽

Drug Effects ◽

Lassa Fever ◽

Interferon Α ◽

Haemorrhagic Fever ◽

Valley Fever

RNA viruses of the families Arena-, Bunya-, Filo-, Flavi-and Togaviridae cause illness in humans ranging from mild, non-specific febrile syndromes to fulminant, lethal haemorrhagic fever. They are transmitted from animals to humans and from human to human by arthropods, aerosols or contact with body fluids. Antiviral compounds, convalescent plasma and interferon inhibit many of these agents in vitro and in virus-infected animals. Drug or plasma treatment is now in use for several human diseases, and would probably be beneficial for a number of others for which there is only limited treatment experience. Success is linked to early diagnosis and initiation of therapy. Ribavirin is used to treat Lassa fever and haemorrhagic fever with renal syndrome, and would probably be effective for Crimean-Congo haemorrhagic fever and for all New World arenavirus diseases. The value of ribavirin in the early treatment of hantavirus pulmonary syndrome is under evaluation. Convalescent plasma is the therapy of choice for Argentine haemorrhagic fever, and would also probably be effective for other New World arenaviruses and some other infections if a safe supply of plasma could be maintained. Ribavirin and interferon-α have both shown protective efficacy in non-human primates infected with Rift Valley fever virus. No effective therapy has yet been identified for filovirus infections, but results in animal models are encouraging. More clinical research is urgently needed. Even if placebo-controlled drug trials cannot be performed, conscientious reports of the results of therapy in limited numbers of patients can still provide evidence of antiviral drug effects.

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The in vitro leishmanicidal activity of hexadecylphosphocholine (miltefosine) against four medically relevant Leishmania species of Brazil

Memórias do Instituto Oswaldo Cruz ◽

10.1590/s0074-02762011000400015 ◽

2011 ◽

Vol 106 (4) ◽

pp. 475-478 ◽

Cited By ~ 25

Author(s):

Eliane de Morais-Teixeira ◽

Quesia Souza Damasceno ◽

Mariana Kolos Galuppo ◽

Alvaro José Romanha ◽

Ana Rabello

Keyword(s):

Leishmania Species ◽

Leishmanicidal Activity

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Polymerase chain reaction-based identification of New World Leishmania species complexes by specific kDNA probes

Acta Tropica ◽

10.1016/s0001-706x(99)00025-x ◽

1999 ◽

Vol 73 (3) ◽

pp. 283-293 ◽

Cited By ~ 14

Author(s):

S.F Brenière ◽

J Telleria ◽

M.F Bosseno ◽

R Buitrago ◽

B Bastrenta ◽

...

Keyword(s):

Polymerase Chain Reaction ◽

New World ◽

Leishmania Species ◽

Chain Reaction ◽

Species Complexes ◽

Polymerase Chain

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Leishmania spp. parasite isolation through inoculation of patient biopsy macerates in interferon gamma knockout mice

Revista do Instituto de Medicina Tropical de São Paulo ◽

10.1590/s0036-46652010000200004 ◽

2010 ◽

Vol 52 (2) ◽

pp. 83-88 ◽

Cited By ~ 12

Author(s):

Milton Adriano Pelli de Oliveira ◽

Alause da Silva Pires ◽

Rosidete Pereira de Bastos ◽

Glória Maria Collet de Araujo Lima ◽

Sebastião Alves Pinto ◽

...

Keyword(s):

Species Identification ◽

Interferon Gamma ◽

Knockout Mice ◽

New World ◽

Clinical Signs ◽

Leishmania Species ◽

Mouse Strains ◽

Preliminary Results ◽

Immunohistochemical Assay ◽

Leishmania Spp

Isolation of Leishmania parasite and species identification are important for confirmation and to help define the epidemiology of the leishmaniasis. Mice are often used to isolate pathogens, but the most common mouse strains are resistant to infection with parasites from the Leishmania (Viannia) subgenus. In this study we tested the inoculation of interferon gamma knockout (IFNγ KO) mice with biopsy macerates from Leishmania-infected patients to increase the possibility of isolating parasites. Biopsies from twenty five patients with clinical signs of leishmaniasis were taken and tested for the presence of parasites. Immunohistochemical assay (IHC) and conventional histopathology detected the parasite in 88% and 83% of the patients, respectively. Leishmania sp. were isolated in biopsy macerates from 52% of the patients by culture in Grace's insect medium, but 13% of isolates were lost due to contamination. Inoculation of macerates in IFNγ KO mice provides isolation of parasites in 31.8% of the biopsies. Most isolates belong to L. (Viannia) subgenus, as confirmed by PCR, except one that belongs to L. (Leishmania) subgenus. Our preliminary results support the use of IFNγ KO mice to improve the possibility to isolate New World Leishmania species.

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